Ready to Use Ketorolac Formulations

ABSTRACT

Disclosed in certain embodiments is a pharmaceutical composition for parenteral administration comprising:
         an aqueous solution comprising ketorolac or a pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 10 mg/mL; and   a pharmaceutically acceptable excipient;   wherein the formulation is substantially free of alcohol.

This application claims priority to U.S. Provisional Application No.61/405,384 filed Oct. 21, 2010, and U.S. Provisional Application No.61/481,602 filed May 2, 2011, the disclosure of which are both herebyincorporated by reference in their entireties.

BACKGROUND

Ketorolac or 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, isa known non-steroidal anti-inflammatory agent and has analgesic andanti-inflammatory properties. Ketorolac is described in U.S. Pat. No.4,089,969.

Ketorolac has considerably higher analgesic and anti-inflammatoryactivity than many other non-steroid anti-inflammatory drugs. Mostsignificantly, it has higher analgesic activity than morphine, withoutthe well-known side effects of the latter. See, e.g., “Ketorolac—Areview of its pharmacodynamic and pharmacokinetic properties and itstherapeutic potential”, Drugs 39(1): 86-109, 1990.

The drug is currently administered as the racemic mixture orally or byinjection and is commercially available in forms suited for such modesof delivery. Ketorolac tromethamine salt for intramuscular andintravenous administration is available at concentrations ranging from1.5% (15 mg in 1 ml) to 3% (60 mg in 2 mls). Typically, for multi-dosetreatment, the recommended dose is 30 mg of drug every 6 hours. Incertain situations, the drug is given as a loading dose of 30 to 60 mgfollowed by subsequent injections of half the loading dose (15 to 30 mg)every 6 to 8 hours. The total daily dose of the drug as such is in therange of 60-120 mg. The administration of multiple injections is notconvenient or well tolerated by patients and bolus administration of thedrug either intravenously or intramuscularly can result in a higherincidence of side effects.

Ketorolac is also available as oral tablets and nasal spray. However,these formulations are insufficient to manage moderately severe acutepain that requires analgesia at the opioid level, e.g., in a postoperative setting.

Although continuous infusion of ketorolac has been contemplated, thepreparation of such formulations in an acute setting has issues withrespect to dosing errors, safety issues and maintaining a sterile,stable formulation.

There exists a need in the art for a ready to use ketorolac formulationthat is suitable for direct administration to patients for the treatmentof analgesia, e.g., in an acute post-operative setting.

All references disclosed herein are hereby incorporated by reference intheir entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pharmaceuticalcomposition for parenteral administration comprising: ketorolac or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient; wherein the composition requires no dilution priorto administration.

It is an object of the present invention to provide a method of treatinga ketorolac treatable condition comprising administering to a patienthaving a ketorolac treatable condition a composition, a parenteralformulation comprising: ketorolac or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient; wherein thecomposition requires no dilution prior to administration.

It is an object of the present invention to provide a method of reducingdosage administration errors in administering ketorolac comprisingproviding a pharmaceutical composition for parenteral administrationcomprising: ketorolac or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable excipient; wherein the compositionrequires no dilution prior to administration.

It is an object of the present invention to provide a method of reducingpharmaceutical active substance wastage in formulation of ketorolacintroduced by use of partial vial usage, which method comprisesproviding a pharmaceutical composition for parenteral administrationcomprising: ketorolac or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable excipient; wherein the compositionrequires no dilution prior to administration.

It is an object of the present invention to provide a method ofpreparing a pharmaceutical composition comprising combining ketorolac ora pharmaceutically acceptable salt thereof with an excipient to producea pharmaceutical composition for parenteral administration wherein thecomposition requires no dilution prior to administration.

It is an object of the present invention to provide a method ofproviding analgesia while reducing the amount of opioids (i.e., opioidsparing) administered to a patient, the method comprising administeringa ready to use ketorolac parenteral formulation by continuous infusionto a patient in need thereof.

It is an object of the present invention to provide a method ofproviding analgesia while reducing the amount of NSAIDs (i.e., NSAIDsparing) administered to a patient, the method comprising administeringa ready to use ketorolac parenteral formulation by continuous infusionto a patient in need thereof.

The opioid sparing and NSAID sparing formulations may have benefits thatinclude decreased respiratory depression, decreased nausea and vomitingand/or decreased length of hospital stay.

It is an object of the present invention to provide a method ofproviding analgesia comprising administering a bolus dose of ketorolacto achieve a rapid analgesic response, followed by continuous infusionwith a ready to use ketorolac parenteral formulation to maintainanalgesic response. In the methods disclosed herein, bolus dosing canbe, e.g., from about 10 mg to about 50 mg, from about 20 mg to about 40mg, or about 30 mg and continuous infusion can be, e.g., from about 0.5mg to about 5 mg per hour, from about 1 mg to about 4 mg per hour, orfrom about 2 mg to about 3 mg per hour.

It is an object of the present invention to provide a method of reducingthe peak to trough plasma levels of multiple bolus administration ofketorolac comprising administering by continuous infusion, a ready touse ketorolac parenteral formulation to provide analgesia.

It is an object of the present invention to provide a method of reducingpostop illeus comprising administering a ready to use ketorolacparenteral formulation by continuous infusion to a patient in needthereof.

It is an object of the present invention to provide a method of treatinganalgesia (e.g., obtaining minimum effective analgesic concentration“MEAC”) comprising administering by continuous infusion a ready to useketorolac formulation as disclosed herein.

It is an object of the present invention to provide a method of reducingthe daily dose of ketorolac necessary to obtain analgesia comprisingadministering by continuous infusion, a ready to use ketorolacparenteral formulation. In certain embodiments, effective analgesia isobtained with a daily dose from about 50 mg to about 110 mg, from about60 mg to about 80 mg, or from about 78 mg to about 102 mg.

It is an object of the present invention to provide a method of reducingthe peak to trough plasma levels of multiple bolus administration ofketorolac comprising administering by continuous infusion, a ready touse ketorolac parenteral formulation to provide analgesia.

It is an object of the present invention to provide a method of reducingside effects associated with ketorolac comprising administering bycontinuous infusion, a ready to use ketorolac parenteral formulation toprovide analgesia.

The above objects of the invention and others may by the presentinvention which in certain embodiments is directed to a pharmaceuticalcomposition for parenteral administration comprising an aqueous solutioncomprising ketorolac or a pharmaceutically acceptable salt thereof in anamount from about 0.1 mg/mL to about 10 mg/mL; and a pharmaceuticallyacceptable excipient; wherein the formulation is substantially free ofalcohol.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition for parenteral administration comprising an aqueous solutioncomprising ketorolac or a pharmaceutically acceptable salt thereof in anamount from about 0.1 mg/mL to about 1 mg/mL; and from about 0.1% toabout 3% dextrose; wherein the composition is contained in a flexibleintravenous bag; wherein the formulation has a pH from about 6.0 toabout 7.5; and wherein the formulation maintains at least 90% of theamount of ketorolac or a pharmaceutically acceptable salt thereof afterstorage for 6 months.

In certain embodiments, the present invention is directed to apharmaceutical composition for parenteral administration comprising anaqueous solution comprising ketorolac or a pharmaceutically acceptablesalt thereof in an amount from about 0.1 mg/mL to about 1 mg/mL; andtrehalose; wherein the composition is contained in a flexibleintravenous bag; wherein the formulation has a pH from about 6.0 toabout 7.5; and wherein the formulation maintains at least 90% of theamount of ketorolac or a pharmaceutically acceptable salt thereof afterstorage for 6 months.

In certain embodiments, the present invention is directed to apharmaceutical composition for parenteral administration comprising anaqueous solution comprising ketorolac or a pharmaceutically acceptablesalt thereof in an amount from about 0.1 mg/mL to about 1 mg/mL; andfrom about 0.1% to about 10% trehalose; wherein the composition iscontained in a flexible intravenous bag; wherein the formulation has apH from about 6.5 to about 7.3; and wherein the formulation maintains atleast 90% of the amount of ketorolac or a pharmaceutically acceptablesalt thereof after storage for 6 months.

In certain embodiments, the present invention is directed to apharmaceutical composition for parenteral administration comprising anaqueous solution comprising ketorolac or a pharmaceutically acceptablesalt thereof in an amount from about 0.1 mg/mL to about 1 mg/mL; and apharmaceutically acceptable excipient; wherein the composition has anactivation energy (E_(a)) of at least 60 kJ/mol; and wherein theformulation maintains at least 90% of the amount of ketorolac or apharmaceutically acceptable salt thereof after storage for 6 months.

The term “ketorolac” means ketorolac free acid or any pharmaceuticallyacceptable salt thereof, e.g., ketorolac tromethamine. The term also ismeant to encompass the racemate as well as the dextro and levo isomers.

The term “ready to use” means a formulation that does not need to becompounded at the time of administration or at a time just prior (e.g.,1 hour, 12 hours, 24 hours, 1 day, 3 days or 7 days) to administrationof the formulation.

The concentrations of ketorolac disclosed herein can be calculated basedon the salt form as an equivalent amount of the free acid form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the one and two year purity projections for formulations7, 8 and 10.

DETAILED DESCRIPTION

The present invention is directed to a pharmaceutical composition forparenteral administration comprising: ketorolac or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient in aready to use formulation, i.e., wherein the composition is requires nodilution prior to administration is suitable for administration at thepoint of manufacture, without the need for hospital personnel to diluteand/or prepare parenteral formulations contemporaneous with use. Theexcipients utilized in the present invention can include, e.g., asolubilizing agent, antioxidant (e.g., vitamin E, vitamin C orglutathione), buffering agent, acidifying agent, complexation enhancingagent, saline, dextrose, lyophilizing aid, bulking agent, stabilizingagents, electrolyte, another therapeutic agent, alkalizing agent,antimicrobial agent, antifungal agent or a combination thereof.

The present invention meets the unmet need of a ready to use storagestable ketorolac formulation wherein it is not necessary for hospitalpersonnel to rely upon admixed formulations that are prepared from acommercially available concentrated product. Admixing a concentratedproduct has the potential to lead to undesired consequences such as anunsterile product, an unstable product, dosing errors, safety issues forstaff.

In certain embodiments, the present invention provides a storage stablepharmaceutical formulation of ketorolac in unconcentrated form. Theseformulations are stable for extended periods even with the increasedsolvent:drug ratio and container surface:drug ratio as compared toconcentrated formulations, which would be expected to lead to increaseddegradation of the drug. Further, the commercially availableconcentrated product contains ethanol which is generally not desirableto be administered to a patient or included in flexible plasticcontainers for an extended period.

In certain embodiments, the formulations of the present inventionmaintain at least 90% of the amount of ketorolac or a pharmaceuticallyacceptable salt thereof after storage for 6 months; maintain at least90% of the amount of ketorolac or a pharmaceutically acceptable saltthereof after storage for 1 year; or maintain at least 90% of the amountof ketorolac or a pharmaceutically acceptable salt thereof after storagefor 2 years.

In certain embodiments, the formulations of the present inventionmaintain at least 95% of the amount of ketorolac or a pharmaceuticallyacceptable salt thereof after storage for 6 months; maintain at least95% of the amount of ketorolac or a pharmaceutically acceptable saltthereof after storage for 1 year; or maintain at least 95% of the amountof ketorolac or a pharmaceutically acceptable salt thereof after storagefor 2 years.

In certain embodiments, the formulations of the present inventionmaintain at least 98% of the amount of ketorolac or a pharmaceuticallyacceptable salt thereof after storage for 6 months; maintain at least98% of the amount of ketorolac or a pharmaceutically acceptable saltthereof after storage for 1 year; or maintain at least 98% of the amountof ketorolac or a pharmaceutically acceptable salt thereof after storagefor 2 years.

In certain embodiments, the ketorolac or a pharmaceutically acceptablesalt thereof is present in the formulation in an amount from about 0.01mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, fromabout 0.25 mg/mL to about 1 mg/mL, or about 0.3 mg/mL, or about 0.4mg/mL, or about 0.5 mg/mL, or about 0.6 mg/mL, or about 0.7 mg/mL, orabout 0.8 mg/mL, or about 0.9 mg/mL.

In certain embodiments, the pH of the ready to use solution has is fromabout 2.5 to about 8.5, from about 3.5 to about 7.5, from about 3.5 toabout 5.5, from about 3.5 to about 4.5, from about 4.5 to about 8.5,from about 4.5 to about 7.5, from about 6.8 to about 7.6, or from about6.9 to about 7.5.

The pH of the compositions of the present invention can be modified byutilizing a sufficient amount of a pH adjuster selected from the groupconsisting of an acid and a base. Suitable pH adjusters typicallyinclude at least an acid or a salt thereof, and/or a base or a saltthereof. Acids and bases can be added on an as needed basis in order toachieve a desired pH. For example, if the pH is greater than the desiredpH, an acid can be used to lower the pH to the desired pH. Acidssuitable for use in premixed pharmaceutical compositions include, butare not limited to, hydrochloric acid, phosphoric acid, citric acid,ascorbic acid, acetic acid, sulphuric acid, carbonic acid and nitricacid. In some embodiments, hydrochloric acid is used to adjust the pH.By way of another example, if the pH is less than the desired pH, a basecan be used to adjust the pH to the desired pH. Bases suitable for usein premixed pharmaceutical compositions include, but are not limited to,sodium hydroxide, potassium hydroxide, calcium hydroxide, sodiumcarbonate, sodium citrate, sodium acetate, and magnesium hydroxide.

The parenteral compositions described herein can also utilize apharmaceutically acceptable buffer. Suitable buffers include, but arenot limited to, pharmaceutically acceptable salts and acids of acetate,glutamate, citrate, tartrate, benzoate, lactate, histidine or otheramino acids, gluconate, phosphate, malate, succinate, formate,propionate, and carbonate. In certain embodiments, the buffer can beincluded in the composition of the present invention in a amount fromabout 0.0001 mg/mL to about 100 mg/mL, from about 0.0001 to about 0.001mg/mL, from about 0.001 to about 0.01 mg/mL, from about 0.01 to about0.1 mg/mL, from about 0.1 to 1 mg/mL, from about 1 to about 5 mg/mL,from about 5 to about 10 mg/mL, from about 10 to about 15 mg/mL, fromabout 15 to about 20 mg/mL, from about 20 to about 25 mg/mL, from about25 to about 50 mg/mL, from about 50 to about 75 mg/mL, or from about 75to about 100 mg/mL.

In other embodiments, the buffer is at least one member selected fromthe group consisting of at least one of (1) a carboxylic acid, a hydroxycarboxylic acid, a dicarboxylic acid, with at least of its acid grouppKa(s) greater than 3.0, a salt thereof, or a mixture of said carboxylicacid and said salt thereof and (2) an alkali metal or ammoniumcarbonate, alkali metal or ammonium bicarbonate, or mixtures thereof.

In alternative embodiments, the can be, e.g., an acetate buffer, anamino acid buffer, a lactobionic acid buffer, or a carbonate buffer.

Amino acids that can be utilized in the present invention include, e.g.,arginine, glycine, methionine or lysine. In certain embodiments, theamino acid has at least one basic group with a pKa of over 5, over 6,over 7 over 8 or over 8.5, or mixtures thereof or a salt thereof, or amixture of an amino acid and said salt. The amino acid can be present inan amount, e.g., from about 0.1 mg/mL to about 100 mg/mL, from about 1mg/mL to about 50 mg/mL or from about 5 mg/mL to about 25 mg/mL.

Carboxylic acids that can be utilized in the present invention include,e.g., gluconic acid, glucuronic acid, gluconic acid ethers, glucuronicacid ethers, carbonic acid alkali metal salts, carbonic acid ammoniumsalts and mixtures thereof.

The parenteral compositions of the present invention can be hypotonic,isotonic or hypertonic. Preferably, the parenteral formulations have atonicity from about 250 to about 350 mOsm/kg.

Any pharmaceutically acceptable tonicity agent can be utilized in theformulations of the present invention. Suitable tonicity agents include,but are not limited to, anhydrous or hydrous forms of sodium chloride,dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol,potassium chloride, mannose, calcium chloride, magnesium chloride andother inorganic salts. Preferably, the tonicity agent is dextrose orsodium chloride.

The tonicity agent can be utilized in the formulations of the presentinvention in an amount, e.g., from about 0.1 mg/mL to about 100 mg/mL,from about 1 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 10mg/mL, from about 30 mg/mL to about 70 mg/mL, from about 1 mg/mL toabout 10 mg/mL, from about 5 mg/mL to about 15 mg/mL, from about 65mg/mL to about 75 mg/mL, or from about 70 mg/mL to about 80 mg/mL.

In embodiments, with dextrose, the amount can be, e.g., from about 0.1%to about 10%, from about 0.2% to about 5%, from about 0.3% to about 3%,or from about 0.5% to about 1.5%.

In order to obtain the ready to use formulation of the presentinvention, a cosolvent for the ketorolac can be utilized. The cosolventcan include a glycol (e.g., polyethylene glycol, propylene glycol),ethanol, or a polyhydric alcohol (e.g., sorbitol, mannitol, xylitol).The cosolvent can be utilized in the present invention, e.g., in anamount from about 0.1 mg/mL to about 150 mg/mL, in an amount from about1 mg/mL to about 75 mg/mL, from about 50 mg/mL to about 100 mg/mL, fromabout 30 mg/mL to about 90 mg/mL, from about 1 mg/mL to about 10 mg/mL,from about 5 mg/mL to about 15 mg/mL, from about 75 mg/mL to about 100mg/mL, or from about 85 mg/mL to about 125 mg/mL.

Preferably, the formulations of the present invention do not containethanol. In embodiments that include ethanol have a preferableconcentration of less than 10% v/v, less than 7.5% v/v, less than 5%v/v, less than 2% v/v, less than 1% v/v or less than 0.5% v/v.

In certain embodiments of the present invention, the pharmaceuticallyacceptable excipient comprises trehalose in an amount, e.g., from about0.1 mg/mL to about 100 mg/mL, from about 1 mg/mL to about 50 mg/mL, fromabout 50 mg/mL to about 10 mg/mL, from about 30 mg/mL to about 70 mg/mL,from about 1 mg/mL to about 10 mg/mL, from about 5 mg/mL to about 15mg/mL, from about 65 mg/mL to about 75 mg/mL, or from about 70 mg/mL toabout 80 mg/mL. In certain embodiments, the trehalose is in an amount,e.g., from about 0.1% to about 10%, from about 0.2% to about 5%, fromabout 0.3% to about 3%, or from about 0.5% to about 1.5%.

The parenteral formulations of the present invention can also include asurfactant, e.g., a non-ionic surfactant. The surfactant can be in anamount, e.g., from about 0.1 mg/mL to about 20 mg/mL, about 0.2 mg/mL toabout 10 mg/mL or from about 1 mg/mL to about 5 mg/mL.

Suitable non-ionic surfactants include but are not limited toethoxylated polysorbate such as polysorbate 80, an ethyleneoxide/propylene oxide copolymer, a polyethoxylated castor oil, or apolyethylene glycol hydroxystearate.

The parenteral formulations of the present invention can include acyclodextrin in order to enhance the solubilization of the ketorolac orpharmaceutically acceptable salt thereof. The active agent can form aninclusion complex with the cyclodextrin, which can be e.g., an alpha,beta or gamma cyclodextrin.

The molar ratio of ketorolac or salt thereof can be, e.g., from about1:10 to about 10:1, from about 1:5 to about 5:1 or from about 1:3 toabout 3:1.

In certain embodiments, the cyclodextrin is a sulfalkylated betacyclodextrin such as sulfobutylated cyclodextrin orsulfobutylether-beta-cyclodextrin. The average degree of substitution ofthe cyclodextrin can be, e.g., from about 2 to about 10 degrees ofsulfobutylation or from about 5 to about 8 degrees of sulfobutylation.In other embodiments, the cyclodextrin is hydroxypropyl betacyclodextrin.

In preferred embodiments, the cyclodextrins of the present invention aresubstantially pure. In particular embodiments, the cyclodextrin has atleast one of the following: (i) less than 100 ppm of a phosphate, (ii)less than 20 ppm of a sulfoalkylating agent, (iii) less than 0.5% wt. ofan underivatized cyclodextrin, (iv) less than 1% wt. of an alkali metalhalide salt or (v) less than 0.25% wt. of a hydrolyzed sulfoalkylatingagent.

In particular embodiments, the cyclodextrin has less than 50 ppm of aphosphate; less than 10 ppm of a sulfoalkylating agent; less than 0.2%wt. of an underivatized cyclodextrin; less than 0.5% wt. of an alkalimetal halide salt; and less than 0.1% wt. of a hydrolyzedsulfoalkylating agent.

In other embodiments, the cyclodextrin has less than 10 ppm of aphosphate; less than 2 ppm of a sulfoalkylating agent; less than 0.1%wt. of an underivatized cyclodextrin; less than 0.2% wt. of an alkalimetal halide salt; and less than 0.08% wt. of a hydrolyzedsulfoalkylating agent.

In further embodiments, the cyclodextrin has less than 5 ppm of aphosphate; less than 0.1% wt. of an alkali metal halide salt; and lessthan 0.05% wt. of a hydrolyzed sulfoalkylating agent.

In certain embodiments, the osmolality of the formulations are e.g.,from about 250 to 350 mOsm/kg, from about 270 to 330 mOsm/kg or fromabout 290 to 310 mOsm/kg.

In certain embodiments, the pharmaceutical compositions of the presentinvention have an activation energy (E_(a)) of at least 60 kJ/mol, atleast 70 kJ/mol, at least 80 kJ/mol, at least 90 kJ/mol, at least 100kJ/mol, or at least 110 kJ/mol.

In certain embodiments, the pharmaceutical compositions are sterilized,e.g., by terminal sterilization.

In certain embodiments, the pharmaceutical composition of the presentinvention has a dissolved oxygen content of less than about 15 mg/L,less than about 12 mg/L or less than about 9 mg/L.

The parenteral compositions of the present invention can be contained ina pharmaceutically acceptable container selected from the groupconsisting of intravenous bags and bottles. The bags and bottles can beglass or a suitable plastic or polymer material. The entire orsubstantially the entire container can be, e.g., selected from the groupconsisting of polyvinyl chloride, polyolefin, polyester, polypropyleneor a combination thereof. In other embodiments, only the surfacematerial that contacts the drug formulation comprises these materials.Non-limiting examples of intravenous bags include, but are not limitedto: Galaxy®, Intravia®, Solomix®, Stedim 71®, Stedim 100®, Viaflex®,Excel®, Visiv®, Viaflo®, Addease®, Addvantage®, Duplex®, First Choice®,Propyflex®, B. Braun® and BFS®. Other embodiments can use containersmanufactured by Pisa® or containers utilizing materials manufactured byTechnoflex®.

The bags can have mono or multi (e.g., dual) ports. The bags may also bebifurcated with one section of the bag used for a bolus and the otherused for continuous infusion. Bifurcated bags can also be used to houseketorolac and another active agent separately.

The formulations disclosed herein can have an overcoat or pouch (e.g.,foil or paper) to protect the active substance from light. In otherembodiments, the composition is protected from oxygen by maintaining anitrogen atmosphere in the space between the formulation container andthe overcoat or pouch. In other embodiments, the container (e.g., glassor plastic) can include be manufactured to be light resistant (e.g., anamber bottle or amber bag).

The parenteral ketorolac formulations of the present invention can alsoinclude an amount of an opioid analgesic. The opioid analgesic, alongwith the ketorolac, is in a ready-to use form and can be administered toa patient in need thereof without the need to dilute the product.

The opioid analgesic can be selected from the group consisting of, e.g.,alfentanil, allylprodine, alphaprodine, anileridine, apomorphine,apocodeine, ben-zylmorphine, bezitramide, brifentanil, buprenorphine,butorphanol, carfentanil, clonitazene, codeine, cyclorphen,cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, methylmorphine, metopon, mirfentanil, morphine,morphine-6-glucuronide, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nociceptinlorphanin FQ(N/OFQ), normorphine, norpipanone, ohmefentanyl, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, pholcodine, piminodine, piritramide,propheptazine, promedol, profadol, properidine, propiram, propoxyphene,remifentanil, sufentanil, tapentadol, tramadol, trefentanil, tilidine,nalbuphine, or any opioid having agonist activity at an opioid receptorbelonging to the phenanthrene, morphinan, benzomorphan, methadone,phenylpiperidine, propionanilide 4-anilidopiperidine, 4-arylpiperidines, and 4-Heteroarylpiperidines class, any opioid havingagonist activity at an opioid receptor having the same pentacyclicnucleus as nalmefene, naltrexone, buprenorphine, levorphanol,meptazinol, pentazocine and dezocine, any drug having agonist activityat an opioid receptor which is a fentanyl analog, and prodrugs, analogs,derivatives, pharmaceutically acceptable salts thereof and mixturesthereof in racemic or enantiomeric form.

The ketorolac formulations described herein can also include anadditional NSAID, e.g., salicylates, indomethacin, flurbiprofen,diclofenac, naproxen, piroxicam, tebufelone, ibuprofen, etodolac,nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone,aminopyrone, phenylbutazone, clofezone, oxyphenbutazone, prenazone,apazone, benzydamine, bucolome, cinchophen, clonixin, ditrazol,epirizole, fenoprofen, floctafenin, flufenamic acid, glaphenine,indoprofen, ketoprofen, loxoprofen, meclofenamic acid, mefenamic acid,niflumic acid, phenacetin, salidifamides, sulindac, suprofen, tolmetin,pharmaceutically acceptable salts thereof, and mixtures thereof.

Non-opioid and non-nsaid analgesics can also be combined with ketorolac.Such agents include without limitation acetaminophen and flupiritine.

The following examples are set forth to assist in understanding theinvention and should not, of course, be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now knownor later developed, which would be within the purview of those skilledin the art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

EXAMPLES 1. MATERIALS AND METHODS

The materials listed in Table 1 were purchased from the indicatedsupplier.

TABLE 1 Description of Materials Used Material Supplier Ketorolactromethamine USP Aldrich H₂O (HPLC grade) Fisher D-(+)-trehalosedihydrate Sigma Ammonium acetate Fluka Dextrose monohydrate AldrichSodium phosphate dibasic Aldrich Citric acid Aldrich Ethanol AldrichPhosphoric acid EMD Sodium chloride Sigma 1.0N HCl BDH 1.0N NaOHMallinckrodt VWR 0.2 μm syringe filters VWR Baxter IntraVia Bags VWR

The development, manufacture, and analysis of all formulations wasperformed using the equipment listed in Table 2.

TABLE 2 Description of Equipment Used to Manufacture and AnalyzeFormulations Description Model Number VWR Stability Oven 1370FM VWRStability Oven 1370FM VWR Stability Chamber 9005L Agilent HPLC 1200Agilent HPLC 1260 Barnstead Autoclave AS12 Thermo Scientific pH MeterOrion 3 Star *Autoclave located at Validation Resources, Bend, OR

The utilized HPLC method for purity analysis method is provided in Table3:

TABLE 3 HPLC Parameters and Integration Events for the Purity MethodHPLC Run Parameters Column Agilent Eclipse XDB-C18 4.6 × 150 mm (S/N:USKH048453) Mobile Phase 55:44:1 MeOH:H₂O:AcOH Run time 15 minutesRetention time Approximately 5.6 min Flow rate 1.2 mL/min Injectionvolume 10 μL Observation wavelength 254 nm, bandwidth = 16 Columntemperature 27° C. Integration Events Skim valley ratio 20.0 Slopesensitivity 0.7 Peak width 0.02 Area reject 1.0 Height reject 0.1Integration cutoff <1.4 min

Generation of Degradation Products:

Degradation products for ketorolac tromethamine were generated underacidic and basic conditions for reference when evaluating HPLCchromatograms for purity. This ensures differentiation betweendegradants, impurities, and peaks which are both impurities anddegradants. For the acid-catalyzed degradation, 4.92 mg of ketorolactromethamine was added to a scintillation vial, followed by 10 mL ofH₂O, and the pH of the resulting colorless solution was adjusted to pH1.60 with H₃PO₄. Aliquots of this solution were placed in capped amberHPLC vials in an 85° C. oven for the indicated amount of time, thenanalyzed by HPLC using the purity method outlined in Table 3. For thebase catalyzed degradation, 4.92 mg of ketorolac tromethamine was addedto a scintillation vial, followed by 10 mL of H₂O, and the resultingcolorless solution was adjusted to pH 12.09 with NaOH. Aliquots of thissolution were placed in capped amber HPLC vials in an 85° C. oven forthe indicated amount of time, then analyzed by HPLC using the puritymethod outlined in Table 3. Table 6 summarizes the measured purity ofketorolac tromethamine after the indicated time.

Light Stability Study:

Ketorolac tromethamine (4.97 mg) was added to a scintillation vial, then10 mL of H₂O was added volumetrically to produce a colorless solution.The clear scintillation vial was capped and placed on the windowsill,exposing the solution to both ambient light and temperature conditions.Aliquots (500 μL) were removed at various time points and diluted withan equal volume of H₂O in an amber HPLC vial. The diluted solution wasthen analyzed by HPLC for the purity of ketorolac tromethamine. Resultsare summarized in Table 11.

Stability Study A in HPLC Vials:

Stability study A was completed in amber HPLC vials to eliminate thepotential incompatibility of a formulation with the RTU bag material.All formulations were prepared in 25 mL class A volumetric flasks. Table4 lists the amounts of the given components in each formulation.

TABLE 4 Compositions of Formulations 1-12 Formulation 1 2 3 4 5 6 7 8 910 11 12 Ketorolac 12.63 12.69 12.64 12.65 12.39 12.39 12.66 12.39 12.5812.71 12.47 12.71 tromethamine (mg) Sodium 219.86 219.30 219.79 219.12219.11 219.55 219.12 219.17 219.01 219.15 219.54 219.73 chloride (mg)Ammonium 19.28 19.28 19.28 19.28 acetate (mg) Citric acid (mg) 68.3468.48 68.79 68.39 Sodium 617.54 617.84 617.62 617.40 phosphate dibasic(mg) Hydrochloric pH ↓ pH ↓ pH ↓ pH ↓ pH ↓ pH ↓ pH ↓ pH ↓ acid Sodium pH↑ pH ↑ pH ↑ pH ↑ pH ↑ pH ↑ pH ↑ pH ↑ hydroxide Water qs to qs to qs toqs to qs to qs to qs to qs to qs to qs to qs to qs to 25 mL 25 mL 25 mL25 mL 25 mL 25 mL 25 mL 25 mL 25 mL 25 mL 25 mL 25 mL Ethanol (μL) 250250 250 Trehalose (mg) 250.19 250.01 249.66 Dextrose (mg) 250.15 250.47250.69 Ketorolac 505.2 507.6 505.6 506.0 495.6 495.6 506.4 495.6 503.2508.4 498.8 508.4 concentration (μg/mL) Osmolarity 303.7 474.2 323.6493.9 727.4 899.4 329.1 349.1 753.8 358.2 378.8 783.8 (mOsmol/L) FinalpH 7.50 7.38 6.89 7.04 7.04 7.05 7.51 7.04 7.02 7.40 7.00 7.05

Once all the components had been added to the flask, the flask wasfilled to the line with H₂O and mixed using a magnetic stir bar untilcompletely in solution. The pH of the formulation was adjusted to thevalue given in Table 4 using 1.0N NaOH or 1.0N HCl. Each formulation waspurged with N₂ for 5 minutes, then the solution was filtered through a0.2 μm syringe filter before 1.6 mL aliquots were transferred into 14separate amber HPLC vials. Seven vials were then capped, while theheadspace of the remaining 7 vials was purged with N₂ and cappedimmediately. Twelve vials were then placed in a 121° C. oven for 20minutes to simulate autoclave conditions. Following the simulatedautoclave conditions, the samples were transferred into the 40° C./75%RH stability chamber to initiate the stability study. At times of 0, 1,4, 7, 10 and 14 days, the sample was removed from the stability chamberand analyzed by HPLC for the purity of ketorolac tromethamine within 24hours. The purity results for all formulations are list in Table 7.

Stability Study B in Baxter IntraVia Bags:

Stability formulations were prepared in 2 L class A volumetric flasks,using the materials listed in Table 5:

TABLE 5 Composition of Formulations 7, 8, and 10 for RTU Bag StabilityStudy Formulation #7 Formulation #8 Formulation #10 Ketorolac 1,00047 g1.00048 g 1.00093 g tromethamine Sodium chloride 17.542 g 17.536 g17.532 g Trehalose 20.015 g 20.011 g — Dextrose — — 20.008 g Ammoniumacetate — 1.544 g — Water qs to 2 L qs to 2 L qs to 2 L pH 7.45 6.947.38 Osmolarity 329.3 329.2 358.2 (mOsmol/L) Ketorolac 500.2 500.2 500.5concentration (μg/mL)

Once all materials were added to the volumetric flask, it was filled tothe line with H₂O. The flask was magnetically stirred if any undissolvedmaterial was present. If necessary, the pH of the formulation wasadjusted using 1.0N NaOH or 1.0N HCl to the final value given in Table5. The formulations were then purged with N₂ for 5 minutes before thebag filling process began. The Baxter IntraVia bags were filled by mass(80 g±1 g) using a peristaltic pump to feed the solution into each bag.A 2-way valve were placed in the solution filling line for sterilefiltration and to regulate flow, respectively. For each formulation, 24bags were filled.

All bags were used in the stability study without exposure to autoclave(or simulated autoclave) conditions. All bags were pulled within 1 daytime points of 0, 4, 7, 14, 28 and 42 days and allowed to equilibrate toroom temperature before sampling. Sampling of the bags for HPLC analysisoccurred using a 5 cc disposable syringe with 21 gauge needle throughthe drug injection port. Approximately 1.5 mL of each formulation wastransferred to an amber HPLC vial and analyzed within 12 hours ofsampling. Results from the purity analysis are summarized in Table 8.

Determination of Osmolarity:

The osmolarity of the individual formulations were determined as per USP<785> guidelines, using equation (1):

$\begin{matrix}{{{Osmolarity}\mspace{14mu} \left( {{mOsmol}\text{/}L} \right)} = {\left( \frac{{{wt}.\mspace{11mu} {of}}\mspace{14mu} {substance}\mspace{11mu} \left( {g\text{/}L} \right)}{{mol}\mspace{14mu} {{wt}.\; (g)}} \right) \times \left( {{number}\mspace{14mu} {of}\mspace{14mu} {species}} \right) \times (1000)}} & (1)\end{matrix}$

The osmolarity of each individual component in the formulation iscalculated and the sum of these values (the total osmolarity) is thevalue provided in tables 4 and 5 for the glass and bag stabilitystudies, respectively.

Stability Predictions Using the Arrhenius Equation:

Long-term stability predictions were completed using Agere's stabilityprediction algorithms, based on the Arrhenius equation (2):

$\begin{matrix}{k = {Ae}^{\frac{- E_{a}}{RT}}} & (2)\end{matrix}$

Where k is the rate constant, A is the pre-exponential factor, E_(a) isthe activation energy, T is the temperature (in degrees Kelvin), and Ris the gas constant (taken to be 8.31446 J·mol⁻¹·K⁻¹). The acquired HPLCpurity data is plotted and fit to a trend line, then the Arrheniusequation parameters are extrapolated to determine the rate constant at agiven temperature. This rate constant represents the rate of degradationof ketorolac tromethamine. Using this rate constant, the long-termstability of a formulation can be predicted. The values of theextrapolated Arrhenius parameters are supplied in Table 10.

2. RESULTS AND DISCUSSION

Acid- and base-catalyzed degradation experiments were performed. After40 hours, both conditions provided significant degradation, affordingchromatograms with identifiable degradation peaks. As reported in Gu, L.et al. (International Journal of Pharmaceutics. (1988), 41, 95-104)there are two primary degradation pathways for ketorolac tromethamine(Scheme 1):

Table 6 summarizes the purity of ketorolac tromethamine measured by HPLCin the acid- and base-catalyzed degradation experiments. The number ofdegradation peaks observed in the base-catalyzed experiment is higher,although the magnitude (and integral of) the degradation peaks in theacid-catalyzed experiment is greater, yielding a lower purity.

TABLE 6 HPLC Purity of Ketorolac Tromethamine Under Acid- andBase-catalyzed Degradation Conditions Condition 1.5 hours 2.5 hours 4hours 24 hours 40 hours Acid 99.02% 98.96% 98.92% 98.87% 98.08% Base99.67% 99.66% 99.62% 99.28% 98.97%

HPLC purity of formulations in amber HPLC vials is provided in Table 7.N₂ headspace has little effect on all formulations and was not includedas a parameter.

TABLE 7 HPLC Purity of Stage II Formulations Pre- Formulation N₂Headspace autoclave 0 days 1.5 days 4 days 6.5 days 10.5 days 14 days1 + 99.75 99.75 99.75 99.75 99.75 99.75 99.74 − 99.75 99.75 99.75 99.7599.75 99.75 99.75 2 + 99.74 99.73 99.74 99.74 99.74 99.73 99.74 − 99.7399.73 99.74 99.74 99.74 99.73 99.73 3 + 99.75 99.75 99.75 99.75 99.7699.75 99.75 − 99.75 99.75 99.75 99.76 99.76 99.75 99.75 4 + 99.74 99.7599.75 99.75 99.75 99.75 99.75 − 99.75 99.74 99.74 99.75 99.75 99.7499.75 5 + 99.75 99.75 99.71 99.70 99.70 99.67 99.67 − 99.76 99.75 99.7399.71 99.70 99.67 99.67 6 + 99.75 99.75 99.75 99.75 99.76 99.75 99.75 −99.76 99.75 99.75 99.76 99.75 99.75 99.75 7 + 99.74 99.74 99.74 99.7499.75 99.74 99.75 − 99.74 99.74 99.74 99.75 99.75 99.74 99.74 8 + 99.7499.75 99.75 99.75 99.76 99.74 99.75 − 99.74 99.74 99.75 99.76 99.7599.75 99.75 9 + 99.74 99.74 99.72 99.71 99.70 99.67 99.67 − 99.76 99.7599.72 99.71 99.70 99.67 99.69 10 + 99.74 99.74 99.75 99.75 99.75 99.7599.75 − 99.75 99.75 99.75 99.75 99.75 99.75 99.75 11 + 99.73 99.73 99.7399.73 99.73 99.73 99.73 − 99.73 99.73 99.73 99.73 99.73 99.73 99.73 12 +99.76 99.54 99.42 99.38 99.20 98.57 98.56 − 99.76 99.46 99.58 99.5399.44 98.94 98.40

This study included 3 formulations at 3 different temperatures (40° C.,60° C., and 80° C.) with time points over 6 weeks. Stability Study Aprovided information to structure Stability Study B with respect to theideal parameters. The primary difference between the two studies is theneed to sample from the Baxter IntraVia bags, which showed degradation.The two-port IntraVia bags were stable and showed no degradation at 40°C., while at 60° C. and 80° C. the bags began to melt to the aluminumfoil on which they were placed over time. The ports began to becomebrown and a salty residue was observed on the outside of the port uponsampling. Table 8 details the measured purity by HPLC of formulations 7,8, and 10.

TABLE 8 HPLC Purity of Formulations 7, 8, and 10 in Baxter IntraVia BagsTemp Formulation (° C.) t = 0 1 day 2 days 4 days 7 days 14 days 28 days42 days 7 40 99.77 99.76 99.76 99.75 99.74 99.75 60 99.77 99.76 99.7799.75 99.77 99.68 80 99.77 99.76 99.76 99.70 99.71 99.59 98.67 8 4099.78 99.75 99.76 99.75 99.74 99.74 60 99.78 99.76 99.76 99.75 99.7299.69 80 99.78 99.75 99.75 99.71 99.68 99.50 98.85 10 40 99.77 99.7699.76 99.75 99.76 99.75 60 99.77 99.76 99.77 99.76 99.71 99.67 80 99.7799.77 99.76 99.73 99.59 98.61 97.19

As experienced in the Stability Study A, all formulations exhibitedminimal degradation at 40° C., while at 60° C. the formulations showonly slight degradation. Only at 80° C. do all formulations start todegrade at a higher rate. This observation is supported by therelatively high activation energies extrapolated from the Arrheniusequation (provided in Table 10). The degradation of ketorolactromethamine observed in this study requires substantial amounts ofenergy, only achievable with high temperatures. The one and two yearpurity projections are given in Table 9 and plotted in FIG. 1.

TABLE 9 Projected Purity of Formulations in Baxter IntraVia Bags at 25°C. Formulation Initial purity Projected (1 year) Projected (2 years) 799.77 99.72 99.66 8 99.78 99.68 99.59 10 99.77 99.75 99.73

Alternative degradation mechanisms exist for ketorolac tromethaminewhich do not necessitate high temperature but rather exposure to ambientlight sources. The ambient light stability study affords results are setforth in Table 11.

TABLE 10 Extrapolated Values of Arrhenius Equation Parameters R² forln(A) vs. Formulation E_(a) (kJ/mol) ln(A) k at 25° C. 1/T plot 7 81.5424.08 1.483E−04 0.933 8 71.34 20.51 2.557E−04 0.918 10 113.00 35.755.379E−05 0.964

TABLE 11 HPLC Purity of Ambient Light Stability Samples Pull Time (days)Purity 0 99.62% 1 99.62% 3 99.60% 5 99.61% 12 99.60% 41 97.03% 48 96.24%62 93.27% 76 90.50%

Following the 42 day stability pull of formulations 7, 8, and 10 inBaxter IntraVia bags, the pH of the formulations were measured forcomparison to the initial value. The results of these measurements aretabulated in Table 12.

TABLE 12 pH change of Formulations in Baxter IntraVia Bags Formulation 7Formulation 8 Formulation 10 Initial pH (t = 0) 7.5 6.9 7.4 40° C. (t =42 days) 7.1 7.5 4.6 60° C. (t = 42 days) 6.9 6.1 5.7

A number of factors can have a significant effect on the measured pH ofthe solution. Primarily, extended exposure to high temperatures canconcentrate the samples contained in the bag by evaporation through thesemi-permeable bag material, as evidenced by the measured concentrationsof the longer-term, high temperature stability samples. Alternatively,carbon dioxide can be absorbed through the bag material, which is thenconverted to carbonic acid in solution. In formulation 8 (containingammonium acetate), ammonia gas can be absorbed into the bag material,leaving the acetate anion which becomes protonated in solution to formacetic acid. All of these situations can alter the pH of a formulation,however, all of these measured pH's are within range of those acceptablefor injectable solutions.

Determination of Dissolved Oxygen:

Procedure:

-   -   1. Samples were transferred to 100 mL BOD bottles and measured        with oxygen meter for dissolved oxygen (Test 1).    -   2. Samples were autoclaved for 15 minutes at 121° C., removed        from autoclave, bottles were immediately capped, and cooled to        room temperature in a water bath, at 24° C. and then measured        with oxygen meter for dissolved oxygen (Tests 2, 3 and 4).

TABLE 13 Dissolved Oxygen Dissolved Dissolved Dissolved Dissolved OxygenOxygen Oxygen Oxygen Formu- mg/L mg/L mg/L mg/L lation Test 1 Test 2Test 3 Test 4 7 9.71 9.68 9.29 9.96 8 9.76 8.32 9.07 9.41 10 9.53 8.849.48 8.98

3. CONCLUSION

Ketorolac tromethamine is shown to be stable upon exposure to heat forextended periods of time. This observation is supported by theextrapolated parameters from the Arrhenius equation, and specifically,the activation energy. The primary risk for a ketorolac-containingformulation is light instability which can be mitigated by use of a foilover pouch to protect from ambient light sources. A predicted stable fora minimum of 2 years is predicted based on, e.g., a formulation asdisclosed herein in Baxter IntraVia bags with the addition of a foilover pouch.

1.-98. (canceled)
 99. A method of preparing a pharmaceutical compositioncomprising combining ketorolac or a pharmaceutically acceptable saltthereof with an aqueous solution and a pharmaceutically acceptableexcipient selected from the a group consisting of trehalose, anhydrousor hydrous forms of sodium chloride, dextrose, sucrose, xylitol,fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose,calcium chloride, and magnesium chloride, wherein the pharmaceuticalcomposition comprises ketorolac or a pharmaceutically acceptable saltthereof in an amount from about 0.1 mg/mL to about 10 mg/mL, wherein thepharmaceutical composition is free of alcohol, and wherein thepharmaceutical composition maintains at least 90% of the amount ofketorolac or a pharmaceutically acceptable salt thereof after storagefor 6 months at 25° C.
 100. (canceled)
 101. A method of preparing apharmaceutical composition for parenteral administration comprising:preparing an aqueous solution comprising ketorolac or a pharmaceuticallyacceptable salt thereof in an amount from about 0.1 mg/mL to about 10mg/mL and a pharmaceutically acceptable excipient selected from the agroup consisting of trehalose, anhydrous or hydrous forms of sodiumchloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol,mannitol, potassium chloride, mannose, calcium chloride, and magnesiumchloride, wherein the pharmaceutical composition is free of alcohol;wherein the pharmaceutical composition maintains at least 90% of theamount of ketorolac or a pharmaceutically acceptable salt thereof afterstorage for 6 months at 25° C.; and filling the aqueous solution into anintravenous container. 102.-107. (canceled)
 108. The method of claim101, further comprising purging the pharmaceutical composition withnitrogen.
 109. The method of claim 101, further comprising subjectingthe pharmaceutical composition to a sterilization step.
 110. The methodof claim 101, wherein the intravenous container is a flexible bag. 111.The method of claim 99, wherein the pharmaceutical composition maintainsat least 90% of the amount of ketorolac or a pharmaceutically acceptablesalt thereof after storage for 1 year.
 112. The method of claim 99,wherein the pharmaceutical composition maintains at least 95% of theamount of ketorolac or a pharmaceutically acceptable salt thereof afterstorage for 6 months.
 113. The method of claim 99, wherein thepharmaceutical composition has a pH from about 4.5 to about 8.5. 114.The method of claim 99, wherein the pharmaceutically acceptable salt isketorolac tromethamine.
 115. The method of claim 99, wherein theosmolality of the pharmaceutical composition is in the range from about250 to 350 mOsm/kg.
 116. The method of claim 99, wherein thepharmaceutical composition has an activation energy (Ea) of at least 60kJ/mol.
 117. The method of claim 99, wherein the pharmaceuticalcomposition has a dissolved oxygen content of less than 15 mg/L. 118.The method of claim 99, further comprising subjecting the pharmaceuticalcomposition to a sterilization step.
 119. The method of claim 101,wherein the pharmaceutical composition maintains at least 90% of theamount of ketorolac or a pharmaceutically acceptable salt thereof afterstorage for 1 year.
 120. The method of claim 101, wherein thepharmaceutical composition maintains at least 95% of the amount ofketorolac or a pharmaceutically acceptable salt thereof after storagefor 6 months.
 121. The method of claim 101, wherein the pharmaceuticalcomposition has a pH from about 4.5 to about 8.5.
 122. The method ofclaim 101, wherein the pharmaceutically acceptable salt is ketorolactromethamine.
 123. The method of claim 101, wherein the osmolality ofthe pharmaceutical composition is in the range from about 250 to 350mOsm/kg.
 124. The method of claim 101, wherein the pharmaceuticalcomposition has an activation energy (Ea) of at least 60 kJ/mol. 125.The method of claim 101, wherein the pharmaceutical composition has adissolved oxygen content of less than 15 mg/L.